title: Synergistic growth inhibition by acyclic retinoid and phosphatidylinositol 3-kinase inhibitor in human hepatoma cells.
abstract: BACKGROUND
  A malfunction of RXRα due to phosphorylation is associated with liver carcinogenesis, and acyclic retinoid (ACR), which targets RXRα, can prevent the development of hepatocellular carcinoma (HCC). Activation of PI3K/Akt signaling plays a critical role in the proliferation and survival of HCC cells. The present study examined the possible combined effects of ACR and LY294002, a PI3K inhibitor, on the growth of human HCC cells.
  
  
  METHODS
  This study examined the effects of the combination of ACR plus LY294002 on the growth of HLF human HCC cells.
  
  
  RESULTS
  ACR and LY294002 preferentially inhibited the growth of HLF cells in comparison with Hc normal hepatocytes. The combination of 1 μM ACR and 5 μM LY294002, in which the concentrations used are less than the IC₅₀ values of these agents, synergistically inhibited the growth of HLF, Hep3B, and Huh7 human HCC cells. These agents when administered in combination acted cooperatively to induce apoptosis in HLF cells. The phosphorylation of RXRα, Akt, and ERK proteins in HLF cells were markedly inhibited by treatment with ACR plus LY294002. Moreover, this combination also increased RXRE promoter activity and the cellular levels of RARβ and p21(CIP1), while decreasing the levels of cyclin D1.
  
  
  CONCLUSIONS
  ACR and LY294002 cooperatively increase the expression of RARβ, while inhibiting the phosphorylation of RXRα, and that these effects are associated with the induction of apoptosis and the inhibition of cell growth in human HCC cells. This combination might therefore be effective for the chemoprevention and chemotherapy of HCC.
authors.affiliation: Department of Gastroenterology, Gifu University Graduate School of Medicine, Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. shimim-gif@umin.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Baba
authors.forename: Masahito
authors.initials: M
authors.lastname: Shimizu
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohno
authors.forename: Yohei
authors.initials: Y
authors.lastname: Shirakami
authors.forename: Masaya
authors.initials: M
authors.lastname: Kubota
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kochi
authors.forename: Daishi
authors.initials: D
authors.lastname: Terakura
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tsurumi
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D049230:Retinoid X Receptor beta / Q000378:metabolism; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002867:Chromones; D019938:Cyclin D1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D048049:Extracellular Signal-Regulated MAP Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D047490:Retinoid X Receptor alpha; D049230:Retinoid X Receptor beta; D014212:Tretinoin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C034534:3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid